A Double-blind Sham Controlled Trial of rTMS in the Treatment of Bipolar Depression

Bipolar affective disorder is a serious mental illness with significant mortality and morbidity [1]. Some estimates of prevalence in Western populations are as high as 6.4% [2]. The depressive aspect of bipolar disorder is often overlooked, possibly due to its less dramatic nature, despite its significant impact on the lives of those who suffer from it [3]. Bipolar depression is associated with a twenty fold increased risk of suicide [4], and typically lasts three to five times as long as a manic or hypomanic episode [5, 6].

Despite this, there has been relatively sparse investigation of treatments for bipolar depression, with guidelines based primarily on expert judgment rather than randomized controlled trials [7]. First line treatment typically involves treatment with a mood stabilizer - lithium, sodium valproate or carbamazepine [7]. Addition of an antidepressant such as an SSRI, buproprion or venlafaxine may be indicated if depression persists, although there is a possibility of inducing rapid cycling and manic or manic episodes. Alternative agents such as lamotrigine and atypical antipsychotics may also be considered [7]. However, there is little firm evidence in this area, and the lack of controlled studies in the treatment of bipolar depression was described by Thase in 2005 [7], as "an embarrassment to the field". In addition to this lack of evidence of efficacy, it is clear that a significant proportion of patients with bipolar depression do not respond to the range of commonly used treatments including medication combinations [8]. It is clear that the depressive phase of bipolar disorder is an important clinical problem and one in which there is a considerable need for the development of new treatments.

rTMS is a technique that was first developed in the mid 1980's which involves the use of a time variable magnetic field to stimulate brain activity. rTMS methods have generally been found to be well tolerated, safe and without complications such as the use of an anesthetic that are required with more invasive forms of brain stimulation such as electroconvulsive therapy.

The ability of rTMS to affect mood was first noted in normal controls in the late 1980's. Studies using focal stimulation of the dorsolateral prefrontal cortex (DLPFC) in depression first appeared in the mid 1990's [9-11]. These studies produced promising results with reduced depression severity following left prefrontal cortex (PFC) stimulation. Since that time a considerable number of trials of left DLPFC rTMS have been conducted. The majority of these studies have used 5-20 Hz stimulation frequency. Most of these have predominately been small in sample size and of short duration (i.e., 10 treatments) (CIA pub 11). They have also been confounded by concerns about the choice of sham stimulation type [12] and variation in stimulation 'dose' provided. The studies with the most robust clinical effects have used a higher number of pulses per subject and higher stimulation intensity levels, suggesting a dose - response relationship (CIA pub 2,11). They have almost exclusively focused on the treatment of patients with unipolar major depression although some of these studies have included a subset of patients with BPAD-DP.

There have been at least 6 meta-analyses of the antidepressant effects of left PFC rTMS. All but one have shown greater antidepressant effects of 2 weeks of HFL-TMS compared to sham; these included an analysis of 6 reports [13], of 12 studies [14], of 16 studies [15], of 10 studies [16] and a Cochrane review of 14 [17]. The single negative study included only 6 reports with 91 subjects and as such had less power than most of the other meta-analyses. Of the larger studies, Holtzheimer et al reported a weighted mean effect size of 0.81 [14], Burt et al reported an effect size of 0.67 [15] and Kozel at al an effect size of 0.53 [16]. These are moderate to large effects. However, the studies repeatedly report that the overall clinical results observed were not that impressive. For example, a mean overall improvement of only 23.8% on the HAMD in the blinded studies reviewed in [14] compared to 7.3% in the sham group.